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Researchers identify gene linked to cell death in dry AMD
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Researchers have identified a gene that, when activated by double-stranded RNA, may be responsible for cell death associated with dry age-related macular degeneration. However, because short-interfering-RNA therapies used for treating wet AMD also appear to activate this gene, these therapies may also increase the risk for dry AMD.
In order to test for an association between the functional toll-like receptor 3 gene (TLR3) variant rs3775291 and AMD, Kang Zhang, MD, PhD, and colleagues genotyped 271 patients with geographic atrophy, 179 patients with choroidal neovascularization and 421 healthy controls, all of whom were of American or European descent. In addition, the researchers examined the influence of TLR3 on human retinal epithelial cells in vitro and on apoptosis of retinal pigment epithelial cells from wild-type mice and Tlr3-knockout (Tlr3-/-) mice after substituting phenylalanine (Phe) for leucine (Leu) at amino acid 412.
The researchers identified a significant link between the T allele Phe variant of rs3775291 and protection against geographic atrophy (P = .005). This association was maintained in two separate case-controlled series testing for geographic atrophy, the authors noted.
However, the researchers found no associations between any TLR3 gene variants and CNV, according to the study.
They also found that the prototypic TLR3 ligand polyinosine-polycytidylic acid, a synthetic double-stranded RNA molecule that activates TLR3, induced apoptosis in more human retinal pigment epithelial cells with the Leu-Leu genotype than those with the Leu-Phe genotype. In addition, TLR3 induced cell death in more wild-type mice than Tlr3-/- mice.
"Since double-stranded RNA can activate TLR3-mediated apoptosis, our results suggest a role of viral [double-stranded] RNA in the development of geographic atrophy and point to the potential toxic effects of short-interfering-RNA therapies in the eye," the study authors said in the New England Journal of Medicine.